The treatment of human illness may be accomplished by administering drugs to the human body via various routes, e.g., oral, sublingual, rectal, parenteral, topical, inhalation, etc. The main advantage of topical delivery of drugs is convenience, with the added benefits that this delivery route avoids bypass metabolism, the risks and inconveniences of intravenous therapy and varied absorption rates and/or gastric emptying times. Topical delivery is generally defined as the application of a drug-containing formulation to the skin to directly treat cutaneous disorders, e.g., acne or the cutaneous manifestations of a general disease, e.g., psoriasis with the intent of containing the pharmacological or other effect of the drug to the surface of the skin or within the skin. Semi-solid formulations in all their diversity dominate the system for topical delivery, but foams, spray, medicated powders, solution, and even medicated adhesive systems are in use.
Topical delivery includes two basic types of product: (1) external topicals that are spread, sprayed, or otherwise dispersed on to cutaneous tissues to cover the affected area and (2) internal topicals that are applied to the mucous membrane orally, vaginally or on anorectal tissues for local activity. For the most part topical preparations are used for the localized effects at the site of their application by virtue of passive drug penetration into the underlying layers of skin or mucous membranes. Although some unintended drug absorption may occur, it is in sub-therapeutic quantities and generally of minor concern.
Under certain circumstances systemic delivery of drugs via topical application of drug-containing compositions to the skin is desirable. However, permeation across the skin first involves partitioning of the drug into the stratum corneum, a layer of the epidermis that is highly impermeable, particularly to hydrophilic molecules like peptides and proteins. For example, small peptides such as thyrotropin-releasing hormone (362 daltons) and vasopressin (356-358 daltons) are known to have difficulty in penetrating the skin barrier. Most substances are believed to diffuse across the stratum corneum via an intercellular lipoidal route, which is a tortuous pathway of limited frictional volume and even more limited productive fractional area in the plane of diffusion. Once through the stratum corneum, topically applied drugs must pass through the dermal region through a system of interlocking channels, through which diffusion is facile and without selectivity. Thus, transdermal systemic delivery of drugs is limited by the poor permeability of some drugs through the skin and limitations of size of drugs that can diffuse through the skin barrier, i.e., less than 500 Daltons. Moreover, because only limited amounts of drugs actually penetrate the skin layers even when penetration enhancers are applied, this route of administration can only be used for drugs that require very small plasma concentration to be effective. For example, the largest daily dose of drug in transdermal patch form is that of nicotine, at a dose of only twenty-one milligrams.
Topical administration of drugs to the eye for local delivery has been used successfully for years, e.g., eye drops for application directly to the eye or percutaneously absorptive compositions for passive diffusion across the skin or upper and/or lower eyelid, however, topical drug delivery for treatment of the posterior segments of the eye poses several problems. The posterior segments of the eye are exquisitely protected from the external environment, which poses unique and fairly challenging hurdles for drug delivery. In particular, the conjunctiva is a unique barrier within the eye with tight cell junctions which inhibit the passage of hydrophilic molecules. Even lipophilic molecules applied to the eye, for example in the form of eye drops, wash over the conjunctiva quickly, resulting in a true contact time of about ninety seconds or less, which is not enough time to permit large quantities to pass through the conjunctiva. It is somewhat dogmatic that topical ocular delivery is insufficient to achieve therapeutic drug levels in the posterior segments.
Topical delivery of drugs to the upper eyelid for local delivery to the anterior segments of the eye has been accomplished through inclusion of an amount of a vasoconstrictor in the topically applied composition or through application of the drug near or along the lash line, effectively applying the drug to the surface of the eyeball over time through blinking action. Inclusion of a vasoconstrictor in certain ophthalmic compositions, particularly those intended to treat glaucoma, for example, has significant drawbacks since the vasoconstrictor restricts blood flow in the immediate area of the eye as well as within the eye, thereby exacerbating the underlying condition.
Thus, there exists a need for methods and compositions for topical administration of drugs for local delivery, such as to the eye and particularly the posterior segments of the eye, as well as for systemic delivery.